Regulation via InsulinRegulation via Glucagon/ Epi

Insulin’s Effect on Glycogen Synthase AND Phosphorylase

Epi and Glucagon

If both synthesis and degradation occurred simulataneously in a cell there would be a futile cycle.

How is such a futile cycle prevented??Glycogen Synthase and Phosphorylase are reciprocally regulated

Glycogen Phosphorylase:

• a homodimeric enzyme, subject to allosteric control.

• It transitions between “relaxed” (active) & “tense” (inhibited) conformations.

• A glycogen storage site on the surface of the Phosphorylase enzyme binds the glycogen particle

“LESS active”

“MORE active”

“LESS active”

“MORE active”

α- Adrenergic Activity in Liver and Ca++

Epi and Glucagon

Muscle and Liver in Exercise

• Liver is taking in lactate converting it to pyruvate, then making glucose via gluconeogenesis and dumping it into bloodstream

• When exercising- that glc is taken up by muscle and used to make more pyruvate/lactate and cycle continues

• When stop exercising- muscle cells stop taking up as much glc- thus liver glc conc goes up- this serves as signal to decrease glycogen breakdown.

Think about this in terms of exercising muscle and how liver helps outLiver cells make glucose! Muscle cells do not. Presence of high conc of glc in cell indicates that blood glucose is adequate= no need to make more glucose.

The cAMP binds to protein kinase A (PKA), a cAMP-dependent protein kinase, activating it. PKA in turn phosphorylates other downstream target proteins including phosphorylase kinase (PhosK) and glycogen synthase (GS). The phosphorylation of PhosK leads to its activation. Conversely, phosphorylation of GS causes its inhibition stopping the formation of glycogen. The activated

PhosK then phosphorylates the next kinase in the chain, glycogen phosphorylase kinase (GPhos). Phosphorylation of GPhos activates the enzyme leading to the release of glucose subunits from glycogen. Thus a chain of phosphorylations leads to the

activation of some downstream signaling components while inhibiting others.

Epi and Glucagon Hormone (epinephrine or glucagon)

via G Protein (G-GTP)

Adenylate cyclase Adenylate cyclase (inactive) (active) catalysis

ATP cyclic AMP + PPi

Activation Phosphodiesterase

AMP

Protein kinase A Protein kinase A (inactive) (active) ATP

ADP

Phosphorylase kinase Phosphorylase kinase (P) (b-inactive) (a-active) Phosphatase ATP

Pi ADP Phosphorylase Phosphorylase (P) (b-allosteric) (a-active)

Phosphatase

Pi

Insulin’s Role in Regulating Glycogen Synthase